Fluorination with Selectfluor ®

Protected D-galactal 5 being nucleophilic at C-2, an addition of an electrophilic fluorine atom on the double bond can then be envisioned. Historically, the first source of electrophilic fluorine used on glycals was molecular fluorine F2 which is highly toxic and very difficult to handle.²⁴ Later on, electrophilic fluorination reagents such as CF3OF, FClO3 and XeF2 were explored and tested with glycals but the results were not fully satisfactory. A major breakthrough in the field of electrophilic fluorination of glycals arose from the discovery of the exceptional properties of Selectfluor^® 10 (1-chloromethyl-4-fluorodiazoniabicylo[2,2,2] bis(tetrafluorobotate)) (Scheme 13). This reagent has the advantages of being mild, safe, and stable besides being an effective source of electrophilic fluorine. Indeed, the fluorine atom in this molecule is bound to a positively charged nitrogen which renders it highly electrophilic. With glycals, Selectfluor^®

27 gives much better results than two other very popular electrophilic fluorination reagents: NFSI (N-Fluorobenzenesulfonimide) 11 and N-Fluoropyridinium 12.

Scheme 13. Structure of commercially available selectfluor^®, NFSI and N-Fluoropyridinium.

The electronic distribution of the enol ether function of D-galactal implies that the C-2 is the most nucleophilic position which means that the addition of the fluorine will be regioselective.

As depicted in Scheme 14, the first step of the reaction mechanism is the formation, in a syn manner, of a 2-fluoro-1-trisalkylammonium intermediate 14.²⁸ The stereoselectivity of this first step is dictated by the steric hindrance of the top face of D-galactal that is mainly due to the substituent at the C-4. It means that the fluorine exclusively reacts from the bottom α face. The second step is the attack of a nucleophile 15 that substitutes the ammonium on the anomeric position. There is a strong debate about the nature of this substitution. It is believed that it is not a pure SN2 process. A mechanistic study²⁸ has shown that increasing the bulk size of the incoming nucleophile in that kind of reaction does change the α/β ratio in favor of the product with the less steric clash. This result suggests a SN1-like process, despite the presence of the fluorine atom.

Scheme 14. Mechanism of the fluorination of D-galactal 5 with Selectfluor^® 10.

This reaction is realized at room temperature in a mixture of water and nitromethane (Scheme 15).²⁹ Nitromethane is chosen as the solvent because it can dissolve the charged Selectfluor salt and it remains inert during the reaction. After consumption of the starting material (monitored by TLC, usually 5 hours), the reaction is heated to reflux for 1 hour so that all the 2-fluoro-1-trisalkylammonium 14 intermediate is hydrolyzed. Glycoside 16 is obtained after purification by silica-gel chromatography with a 68 % yield.

28

Scheme 15. Fluorination of D-galactal with selectfluor bis-tetrafluoroborate 10.

It is known in the literature²² that the counterion of Selectfluor^® can have an effect on the formation of side products and subsequently on the yield. Selectfluor^® is commercially available as a bis-tetrafluoroborate salt. This counter anion is actually a source of nucleophilic fluorine and thus can allow the formation of a 1,2-difluorosaccharide as a side product. Based on that hypothesis, the use of a triflate counterion, which is much less nucleophilic and more soluble in nitromethane, may increase the yield in the desired product. For example, the reported yields for the fluorination of diacetylfucal with benzyl alcohol as the nucleophile varied from 26 % to 72 % when Selectfluor bis-triflate 17 was used instead of commercial Selectfluor^® 10. However, the impact of the counterion effect also depends a lot on the nature of the substrate and on the nucleophilic species that adds to the anomeric center. To test if the same effect could be observed on D-galactal, Selectfluor bis-triflate 17 has been synthesized from commercially available Selectfluor bis-tetrafluoroborate 10 with a 91 % yield (Scheme 16).

Scheme 16. Synthesis of Selectfluor® bis-triflate from commercially available Selectfluor®.

Then, the fluorination of D-galactal was performed with that particular salt to see the effect on the obtained yield after purification (Scheme 17). Unfortunately, the yield (42 %) was actually lower than with the commercial Selectfluor^®. It can be explained by the fact that the reactions were not performed on the same scale. Indeed, minor losses by experimental errors can have a higher impact on the yield with reactions done on small scale. Still, as the yield with standard Selectfluor^® is satisfactory to fulfill our objectives, it has been decided to carry on the fluorination step with commercially available Selectfluor^®.

29

Scheme 17. Fluorination of D-galactal with selectfluor bis-triflate 17.

Once the fluorination step was optimized, the acetyl groups could then be deprotected. For that matter, the Zemplén deacetylation procedure has been followed (Scheme 18).³⁰ It consists in using a catalytic amount of sodium methoxide in methanol to deprotect quickly all the acetyl groups. After complete consumption of the starting material (monitored by TLC, usually 20 minutes), the final crude mixture is passed through a short column of Dowex 50WX8. This resin is an ion-exchange resin with sulfonic acid functional groups that will allow the removal of sodium salts from the desired product. Then the solution is concentrated in vacuo to obtain 6 as a slight yellowish syrup (99 % yield) that eventually solidifies into a white solid after a day at rest.

Scheme 18. Deprotection of the acetyl functions with MeONa to obtain 2-deoxy-2-fluoro-D-galactopyranose.